Hairy cell leukemia is a lymphoproliferative disorder with invasion of the bone marrow and spleen characterized clinically by sytemic cytopenias. We and others have shown that over 90% of these patients show complete or partial responses to therapy with interferon-Alpha (IFN). Although the majoritiy of these patients have normal numbers of circulating natural killer cells (NK) prior to therapy, they all exhibit a marked depression in NK cytolytic activity. In most patients responding clinically to the IFN Therapy, this defect in NK function was corrected to near normal values. This occurred concomittently with the loss of circulating hairy cells and normalization of peripheral blood counts. The research is focused at determining the nature of this immune cell defect, the role of the circulating hairy cell and how IFN might modulate this phenomenon. We will evaluate NK cell function in patients before and during therapy. This will include detemrination of the frequency and efficiency of isolated NK cells, (leu 11+) at the single cell level. To determine whether cells (pre-NK) from this population can be recruited to be functionally active NK cells, we will examine their responsiveness to IFN in vitro. We will also establish B-cell growth factor (BCGF) dependent cell lines form hairy cell leukemia patients. These will be used to determine a) if hairy cells can modulate or suppress normal NK activity, b) if hairy cells can serve as susceptible targets of NK cytotoxicity, and c) the influence of IFN on these parameters. In addition, we will evaluate direct effects of IFN on the kinetics of hairy cell growth in vitro, expression of cellular protooncogenes, and changes in markers of cell differentiation. These studies may provide us with new insights regarding the mechanisms of action of IFN in this responsive disease.